This invention relates to the therapies using the substance amantadine and related compounds particularly memantine and rimantidine.
Amantadine and/or related compounds have been proposed for various therapies. Initially, these compounds were proposed to treat influenza virus. For example, Mullis et al. U.S. Pat. No. 3,391,142 discloses adamantylamines which are said to be antiviral agents. Griffin U.S. Pat. No. 4,351,847 discloses that an amantadine derivative is effective against herpes simplex virus. Smith U.S. Pat. No. 3,328,251 discloses (at 13:24-31) that certain amantadine related compounds are effective against animal viruses, particularly swine influenza.
By chance, it was also observed that amantadine and related compounds are effective against the symptoms of Parkinson's disease. Tominack and Hayden (pp.460-461). See also, Scherm U.S. Pat. No. 4,122,193 at 6:54-60. Braunwald et al. (Principles of Internal Medicine, 11th ed., p. 2017, New York, McGraw Hill, 1987) report that amantadine has been used to treat Parkinson's disease and that its effect is achieved by its capacity to release stored dopamine from presynaptic terminals. See also Merk Index, p.55, #373; p. 1188, #8116; and APP-2, #A7, disclosing the use of various compounds for influenza A, treatment of Parkinsonism, and drug-induced extrapyramidal reactions; one such compound is reportedly being studied in control of micturition and limb muscle mobility, as well as an antispasmodic.
Other uses for such compounds have been proposed. For example, Scherm '193 (at 6:56-60) discloses that certain compounds can be used for treating
"other kinds of hyperkinesis [in addition to Parkinsonism] including head tremors, thalamic tension conditions and spastic conditions, and even for the activation of akinetic cerebroorganic conditions." PA1 apoplexy, open-heart surgery, cardiac standstill, subarachnoidal hemorrhage, transient cerebro-ischemic attacks, perinatal asphyxia, anoxia, hypoglycemia, apnoea and Alzheimer's disease. [Emphasis added.]"
Bormann et al. U.S. Pat. No. 5,061,703 discloses certain amantadine derivatives are useful not only for the treatment of parkinsonian and parkinsonoid diseases, by a mode of action attributed to a dopaminergic influence on the central nervous system (2:38-3:17), but also to reduce neuronal damage associated with cerebral ischemia, which is mediated by the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor. Bormann et al. reports that certain adamantine derivatives ". . . exhibit NMDA receptor channel-antagonistic and anticonvulsive properties." (2:61-63). It also reports (3:10-16) that the adamantine derivatives "are especially suited for the prevention and treatment of cerebral ischemia after
Turski et al. (Nature 349:414, 1991), reports certain experiments investigating the role of excitatory amino acids in dopaminergic toxicity caused by intake of a toxin known as MPTP (1-methyl-4-phenyl-1, 2, 3, 6,-tetra hydropyridine). Excitatory amino acid antagonists were coadministered with MPP.sup.+ (the active metabolite of MPTP), and certain NMDA antagonists offered temporary protection against MPP.sup.+.
Meldrum, Trends Pharm. Sci. September, 1990, vol. 11, pp. 379-387 reviews reported literature concerning the possibility that excitatory amino acid receptor agonists of endogenous or environmental origin contribute to neuronal degeneration in disease states. After reviewing the several known receptors implicated in excitatory amino acid activity (particularly glutamate activity), the authors review (p. 386) suggestions that excitotoxic mechanisms might play a role in the pathogenesis of various chronic neurodegenerative disorders including Huntington's disease, olivo-pontocerebellar atrophy, senile dementia of the Alzheimer type, parkinsonism and amyotrophic lateral sclerosis (ALS), as well as two chronic syndromes linked to plant toxins.
Rothman et al. Trends Neurosci. 10:299-302 (1987) also review literature concerning the possibility that glutamate neurotoxicity may be responsible for neuronal degeneration in various neurological disorders.
Bormann, Eur. J. Pharm. (1989) 166:591-592 reports that memantine blocks NMDA receptor channels.
Kornhuber et al. Eur. J. Pharm. 166:589-590 (1989) report that memantine inhibits the binding of an NMDA antagonist (MK-801) to post-mortem human brain homogenates.
Hahn et al. Proc. Nat'l Acad. Sci. (1988) 85:6556-6560 report that it is widely held that a glutamate-like toxin that resembles NMDA may be responsible for the death of nerve cells seen after severe neurological insults including stroke, seizures, and degenerative disorders, such as Huntington's disease, Alzheimer's disease, and the amyotrophic lateral sclerosis-parkinsonism-dementia complex found on Guam. They report findings suggesting that Ca.sup.++ entry through NMDA-activated channels is responsible for this type of neuronal death and suggest strategies that may be clinically useful in the treatment of various neurological disorders.
Choi, Neuron 1:623-634 report that neurotoxicity due to excitatory amino acids may be involved in slowly progressive degenerative diseases such as Huntington's disease.